Abstract

By interfering with renal growth and development , congenital urinary tract obstruction constitutes one of the most important causes of renal failure in infants and children. Obstructive nephropathy is also a significant cause of renal insufficiency in the adult. Unilateral ureteral obstruction (UUO) activates renal programmed cell death (apoptosis) and the renin-angiotensin system. These responses are greater and more prolonged in the neonate than in the adult. Angiotensin II (ANG II) stimulates transforming growth factor-beta 1 and myofibroblast transformation, which may lead to progression of interstitial fibrosis and tubular atrophy in the obstructed kidney. However, acutely following UUO in the neonatal rat, exogenous ANG II increases tubular cell proliferation and decreases apoptosis in the obstructed kidney. We hypothesize that increased renal generation of ANG II is an early protective response to UUO, but that continued production of ANG Il is maladaptive. In the proposed research plan, the renin-angiotensin system will be selectively inhibited (by enalapril, losartan, or PD123319) or stimulated (by ANG II) in neonatal and adult rats with UUO or sham operation. Renal interstitial ANG II will be measured by microdialysis, and the response to single nephron obstruction will be determined by micropuncture. In addition, transgenic mice with 1-4 copies of the angiotensinogen gene will be subjected to UUO or sham operation. Renal tubular cell disruption (determined by focal contact distribution) and apoptosis (determined by flow cytometry and TUNEL) and their modulators (transforming growth factor-beta 1 , clusterin, and bc1-2) will be examined by analysis of mRNA and protein distribution by immunohistochemistry. Renal interstitial myofibroblast transformation and interstitial fibrosis will also be determined. These studies will elucidate the mechanisms by which the renin-angiotensin system regulates the renal cellular responses to UUO, and may lead to new interventions to avert progression of renal insufficiency in patients with obstructive nephropathy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Specialized Center (P50)
Project #
1P50DK052612-01
Application #
6239291
Study Section
Project Start
1997-09-01
Project End
1998-08-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
University of Virginia
Department
Type
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904

  Publications

Gomez, R Ariel; Belyea, Brian; Medrano, Silvia et al. (2014) Fate and plasticity of renin precursors in development and disease. Pediatr Nephrol 29:721-6
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Lysiak, Jeffrey J; Kirby, Jennifer L; Tremblay, Jacques J et al. (2009) Hypoxia-inducible factor-1alpha is constitutively expressed in murine Leydig cells and regulates 3beta-hydroxysteroid dehydrogenase type 1 promoter activity. J Androl 30:146-56
Reinking, Benjamin E; Wedemeyer, Elesa W; Weiss, Robert M et al. (2009) Cardiomyopathy in offspring of diabetic rats is associated with activation of the MAPK and apoptotic pathways. Cardiovasc Diabetol 8:43
Hinze, Claas H; Suzuki, Michiko; Klein-Gitelman, Marisa et al. (2009) Neutrophil gelatinase-associated lipocalin is a predictor of the course of global and renal childhood-onset systemic lupus erythematosus disease activity. Arthritis Rheum 60:2772-81
Zeng, Chunyu; Villar, Van Anthony M; Eisner, Gilbert M et al. (2008) G protein-coupled receptor kinase 4: role in blood pressure regulation. Hypertension 51:1449-55
Chevalier, Robert L (2008) Chronic partial ureteral obstruction and the developing kidney. Pediatr Radiol 38 Suppl 1:S35-40
Portilla, D; Dent, C; Sugaya, T et al. (2008) Liver fatty acid-binding protein as a biomarker of acute kidney injury after cardiac surgery. Kidney Int 73:465-72
Escano Jr, Crisanto S; Keever, Lindsay B; Gutweiler, Alexander A et al. (2008) Angiotensin II activates extracellular signal-regulated kinase independently of receptor tyrosine kinases in renal smooth muscle cells: implications for blood pressure regulation. J Pharmacol Exp Ther 324:34-42
Li, Hewang; Armando, Ines; Yu, Peiying et al. (2008) Dopamine 5 receptor mediates Ang II type 1 receptor degradation via a ubiquitin-proteasome pathway in mice and human cells. J Clin Invest 118:2180-9

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